The overall aims of this multidisciplinary research program are: 1) to develop principles of bile acid evolution; 2) to eludicate structure-activity-metabolism relationships of natural and synthetic bile acids; and 3) to use these principles to develop new therapeutic approaches to hepatobiliary and digestive disease based on bile acid agonists or antagonists. Experiments to be performed may be grouped as follows. Evolution of bile acids and bile alcohols: The chemical structure of bile acids and bile alcohols in a spectrum of vertebrates will be determined using modern chemical techniques in order to develop principles of bile acid evolution as well as define the value of such analyses for tracing evolutionary relationships. Bile acid pharmacology-toxicology: The influence of side chain structure on bile acid biotransformation will be examined using the C22 (dinor) homologues of natural bile acids to test the hypothesis that these compounds will be poorly amidated, glucuronidated, and hypercholeretic. The biotransformation and chronic toxicity of novel monohydroxy- bile acids (7alphaOH,7betaOH,12alphaOH,l2betaOH) will also be defined to provide information on their potential therapeutic utility as inhibitors of ileal transport. Bile acid physiology: The physiological properties of cholylfluorescein and other bile acid fluorescein conjugates will be defined. Biliary lipid composition (phospholipid and cholesterol) will examined in a spectrum of vertebrates to define the biology of bile acid induced biliary lipid secretion. Efforts to clone the apical Na+/conjugated bile acid cotransporter present in the ileal enterocyte will continue; if unsuccessful, the chromatographic isolation of this membrane-bound protein will be attempted. Bile acid therapeutics: Cholylsarcosine will be tested as a bile acid replacement for bile acid deficiency states in patients with severe bile acid malabsorption because of ileal resection. The efficacy of intravenous bile acids in a rabbit model of TPN-induced cholestasis will be tested. Inhibitors of the ileal transport system for conjugated bile acids will be synthesized and tested. Such compounds should be useful for the treatment of cholestatic liver disease or hypercholesterolemia. Biliary bile acid composition in patients with cholestatic liver disease before and during ursodiol therapy, as well as in patients after liver transplantation, will be analyzed by HPLC. If successful, these experiments will provide new physiological insights and new therapeutic approaches to hepatobiliary and digestive disease.
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